CN101133049B - Process for the preparation of optically active derivatives of 2-(2-pyridylmethylsulfinyl)-benzimidazole via inclusion complex with 1,1'-binaphthalene-2, 2'diol - Google Patents
Process for the preparation of optically active derivatives of 2-(2-pyridylmethylsulfinyl)-benzimidazole via inclusion complex with 1,1'-binaphthalene-2, 2'diol Download PDFInfo
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- CN101133049B CN101133049B CN2006800068718A CN200680006871A CN101133049B CN 101133049 B CN101133049 B CN 101133049B CN 2006800068718 A CN2006800068718 A CN 2006800068718A CN 200680006871 A CN200680006871 A CN 200680006871A CN 101133049 B CN101133049 B CN 101133049B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 30
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 title description 2
- HBDKFZNDMVLSHM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-1h-benzimidazole Chemical class N=1C2=CC=CC=C2NC=1S(=O)CC1=CC=CC=N1 HBDKFZNDMVLSHM-UHFFFAOYSA-N 0.000 title 1
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000000605 extraction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 claims description 20
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- -1 methoxyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 7
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 7
- 229910052728 basic metal Inorganic materials 0.000 claims description 7
- 150000003818 basic metals Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 150000003841 chloride salts Chemical class 0.000 claims 2
- 238000010956 selective crystallization Methods 0.000 claims 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 150000001412 amines Chemical class 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000004587 chromatography analysis Methods 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 229960000381 omeprazole Drugs 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 229960004770 esomeprazole Drugs 0.000 description 15
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 15
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960003174 lansoprazole Drugs 0.000 description 2
- SIXIIKVOZAGHPV-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=C[CH]C2=N1 SIXIIKVOZAGHPV-UHFFFAOYSA-N 0.000 description 2
- KWORUUGOSLYAGD-WLHYKHABSA-N magnesium;5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical class [Mg+2].C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-WLHYKHABSA-N 0.000 description 2
- 229960005019 pantoprazole Drugs 0.000 description 2
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 2
- 229960004157 rabeprazole Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
Process for the preparation of optically active derivatives of 2-(2-piridylmethylsulfinyl)-benzimidazole, or salts thereof, by resolution of the corresponding racemic derivatives of 2-(2-piridylmethylsulfinyl)-benzimidazole. The resolution is performed through the formation of inclusion complexes with (S)-(-) or (R)-(+)-[1,1'-Binaphthalene]-2,2'-diol in the presence of an amine, followed by the break of the inclusion complex by treatment with an hydroxide of an alkaline metal. The enantiomer of the derivative of 2-(2-piridylmethylsulfinyl)-benzimidazole may be obtained by extractions at a particular pH with a suitable organic solvent. The process allows to perform the resolution with high yields and high optical purity, without using neither toxic solvents nor chromatography.
Description
Technical field
The present invention relates to a kind of method for preparing 2-(2-pyridylmethyl sulfinyl)-benzoglyoxaline optically active derivatives from 2-(2-pyridylmethyl sulfinyl)-benzoglyoxaline racemic derivant.
Background technology
The various derivatives of 2-(2-pyridylmethyl sulfinyl)-benzoglyoxaline are called as proton pump inhibitor, and can effectively treat stomach ulcer.What give prominence in these compounds is omeprazole, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline; Lansoprazole, 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl] methyl] sulfinyl]-the 1H-benzoglyoxaline; Pantoprazole, 5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline; And rabeprazole, 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-the 1H-benzoglyoxaline.These compounds are the sulfoxide compounds that have asymmetric center on sulphur atom, and therefore, its racemic mixture form with two kinds of enantiomorphs exists.
In recent years, the preparation of the enantiomorph of pharmacologically active chemical compounds receives much concern, because it demonstrates the pharmacokinetics and the biological property of improvement with respect to racemic mixture.
The enantiomorph of a kind of known 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives is an esomeprazole, and it is as shown in the formula shown in (I).It is racemic product omeprazole (S) enantiomorph.Described S configuration is corresponding to (-)-enantiomorph.
The method of the enantiomorph of several separation omeprazoles was described.In DE 4035455, the method for resolution of omeprazole has been described, it adopts diastereomer ether, with its separation, hydrolysis in acidic solution subsequently.
In EP 652.872-A, described a kind of based on the method for preparing the S-magnesium salt of omeprazole by formation non-enantiomer ester resolution of racemic omeprazole.
In WO 04/2982-A, to have described and drawn the azoles Separation of Enantiomers, it comprises and coordination agent (transition metal), sequestrant (quelatingagent) and organic acid reaction, and separates the diastereomer adducts that obtains subsequently.
At last, in CN 1.223.262, described by forming clathrate complex, the method for resolution of omeprazole with two-beta naphthal, two-2-phenanthrol or tartaric derivative.From clathrate complex, reclaim enantiomorph by chromatography.Under the top condition described in this document, obtain 87% enantiomeric excess (e.e.), but it need use benzene/hexanes mixtures as solvent.Benzene is a kind of high toxicity solvent, therefore is not suitable for using under large-scale operation.With other hydrocarbon polymer such as toluene or dimethylbenzene, the e.e. that obtains is lower than 62%, and this makes this method infeasible under industrially scalable.This method has also shown in the chromatographic typical problem of extensive use down.Similarly, the circulation ratio of the laboratory condition of the preparation required compound of describing in this document shows that in fact, the product total recovery that obtains is lower.At the paper " Resolution of omeprazole by inclusion complexation with achiral host Binol " of Jingen Deng ' s etc.,
Tetrahedron Asymmetry2000, vol.11 has used identical synthetic route among the pp.1729-1732, and the author of above-mentioned paper is the contriver of this patent.Yet unique solvent of description is the benzene/hexanes mixtures that shows aforesaid drawbacks.
Therefore, the method for each single enantiomer of another kind of preparation 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives need be provided.Particularly, if their easy industrialization and not relating to use dangerous solvents, also do not relate to that to separate through chromatographic technique will be very useful.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing each enantiomorph of 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives, particularly obtain each enantiomorph of omeprazole, lansoprazole, pantoprazole and rabeprazole.The contriver have been found that the fractionation of drawing azoles can be in the presence of amine by with replace [1,1 '-dinaphthalene]-2,2 '-one of two enantiomorphs of diphenol form clathrate complex and carry out, and it has high yield and high optical purity, is a kind of method of using dangerous solvents and chromatographic separation that do not relate to.Can be by using suitable organic solvent extraction from clathrate complex, to reclaim the enantiomorph of 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives with alkali-metal hydroxide treatment with under specific pH.
Therefore, according to an aspect of the present invention, provide a kind of preparation formula (I) racemic compound or its salt, with and each method of purified enantiomorph basically of solvate (comprising hydrate),
Wherein, R
1, R
2And R
3Be identical or different group, it is selected from H, (C
1-C
3)-alkyl, the optional (C that is replaced by one or more fluorine atoms
1-C
3)-alkoxyl group and (C
1-C
3)-alkoxyl group-(C
1-C
3)-alkoxyl group; And R
4Be to be selected from H and the optional (C that is replaced by one or more fluorine atoms
1-C
3The group of)-alkoxyl group; Described method comprises:
A) in the mixture of amine and suitable solvent, with [1 of replacement, 1 '-dinaphthalene]-2,2 '-one of two kinds of enantiomorphs of diphenol handle formula (I) compound of racemic mixture form, thereby separate by [1 of a kind of enantiomorph of formula (I) compound and replacement, 1 '-dinaphthalene]-2,2 '-clathrate complex that a kind of enantiomorph of diphenol forms;
B) be used in the clathrate complex that obtains in the alkali-metal hydroxide treatment abovementioned steps in the mixture of water and organic solvent, thereby free alkali form or its salt form of a kind of enantiomorph of the formula of obtaining (I) compound, wherein said organic solvent and water unmixing or miscible hardly; And
C) if obtained the free alkali form of formula (I) compound enantiomorph, randomly, be translated into its salt form.
Basically purified enantiomorph is understood that it has the enantiomeric excess that is enough to mass preparation, and this depends on that those skilled in the art are utilizing the various particular cases that will detect when of the present invention.Usually, enantiomeric excess (e.e.) but be at least described method industrialization in 95% o'clock and use, even if desired, may reach at least 99% e.e. by method of the present invention.
In preferred embodiments, the purified basically enantiomorph of formula (I) compound is such compound, wherein R
1It is methyl; R
2Be 2,2, the 2-trifluoro ethoxy; And R
3And R
4Be hydrogen.In other embodiment preferred, R
1And R
2It is methoxyl group; R
3Be hydrogen; And R
4It is difluoro-methoxy.In other embodiment preferred, R
1It is methyl; R
2It is 3-methoxyl group-propoxy-; And R
3And R
4Be hydrogen.In other embodiment preferred, R
1And R
3It is methyl; And R
2And R
4It is methoxyl group.
The strategy that uses in resolving racemic mixtures is based on by adding the clathrate complex of chiral reagent formation diastereomer feature.As well known by persons skilled in the art, different with enantiomorph, diastereomer has different physical propertiess, solubleness for example, and it makes them separable.Select by experiment [1,1 '-dinaphthalene]-2,2 of the replacement that will use '-enantiomorph of diphenol, with the enantiomorph of formula (I) compound that need to obtain.
Preferably, with (S)-(-) of formula (II)-[1,1 '-dinaphthalene]-2,2 '-diphenol or with (R)-(+) of formula (II ')-[1,1 '-dinaphthalene]-2,2 '-diphenol forms clathrate complex, although can use [1,1 '-dinaphthalene]-2,2 of other replacement '-diphenol.
Therefore, for obtaining the S-omeprazole, by with (S)-(-) of formula (II)-[1,1 '-dinaphthalene]-2,2 '-diphenol handles omeprazole and forms clathrate complex.The enantiomeric excess of the complex compound that obtains with the S-omeprazole is about 97%.
The optimum condition of carrying out described method changes with the parameter that those skilled in the art considered, for example raw material, temperature and similar parameters.Adjust these parameters of each situation, to obtain maximum and clathrate complex 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives.These conditions can be easy to determine by under the help of those skilled in the art by the normal experiment and the method for being instructed in this specification sheets embodiment.
Preferably, the mol ratio of raw material is 0.5～3mol corresponding [1,1 '-dinaphthalene]-2,2 '-diphenol enantiomorph/mol racemic compound.More preferably, mol ratio is 1.2～2mol[1,1 '-dinaphthalene]-2,2 '-diphenol/mol racemic compound.Most preferred mol ratio is 1.5mol corresponding [1,1 '-dinaphthalene]-2,2 '-diphenol/mol racemic compound.
Preferably, solvent for use is aromatic hydrocarbon (as toluene or a dimethylbenzene), or described aromatic hydrocarbon and aliphatic hydrocrbon (C
6-C
8) mixture of (as hexane, hexanaphthene or heptane).Preferably, this solvent is selected from toluene, dimethylbenzene, toluene/heptane mixture, toluene/hexane mixtures, xylene/heptane mixtures and xylene/hexane mixtures.The amount of solvent changes with raw material.Usually this amount is 5～50ml/g.Be preferably 6～37ml/g.More preferably about 12ml/g.
In preferred embodiments, described amine is tertiary amine such as triethylamine, Tributylamine and tripropyl amine.In a more preferred embodiment, described tertiary amine is a triethylamine.The amount of amine changes with raw material.Usually this amount is 0.01～5ml/g.Be preferably 0.1～1ml/g.More preferably about 0.2ml/g.
Usually, the formation of clathrate complex is to carry out to the temperature between the reflux temperature of solvent for use at 20 ℃.Preferably under 50～100 ℃ temperature, carry out.
Can from reaction medium, separate by filtering at the clathrate complex that the fs forms.After the filtration; clathrate complex is by a kind of [1; 1 '-dinaphthalene]-2; 2 '-enantiomorph of diphenol and the formation of the enantiomorph of a kind of 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives, and filtrate mainly comprises other enantiomorph of 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives.
If desired, can carry out once or for several times the recrystallization of clathrate complex to increase e.e..Preferably, use (C
1-C
4) alcohol carries out described recrystallization, preferably uses ethanol, or be used to form a kind of in the solvent of above-mentioned clathrate complex.
For obtaining the enantiomorph (it is the part of clathrate complex) of required 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives, must the described clathrate complex of cracking.This cracking can be undertaken by the alkali metal hydroxide processing that is used in water and the ORGANIC SOLVENT MIXTURES, and described organic solvent and water are unmixings or almost immiscible.
Preferably, alkali metal hydroxide is sodium hydroxide or potassium hydroxide.More preferably, alkali metal hydroxide is a sodium hydroxide.
Also preferably, be selected from (C with water unmixing or almost immiscible organic solvent
6-C
8) aromatic hydrocarbon such as toluene or dimethylbenzene; (C
1-C
3) aliphatic chlorides such as methylene dichloride or chloroform, and (C
2-C
8) aliphatic ether such as ether, isopropyl ether or t-butyl methyl ether.
The amount of solvent and water changes with clathrate complex.Usually, the amount of solvent is 1～30ml/g clathrate complex.Preferred 6～15ml/g.Similarly, the amount of water is generally 1～30ml/g clathrate complex.Preferred 4～15ml/g.
Complex compound is in a single day cleaved, with regard to the pH of conditioned reaction medium and separate each phase.Like this, employed mainly be present in [1,1 '-dinaphthalene]-2,2 in the organic phase '-enantiomorph of diphenol, with the Chiral Separation of the 2-that mainly is present in aqueous phase (2-pyridylmethyl sulfinyl)-benzimidizole derivatives.Preferably, be separated under 10.5～12.5 the pH and carry out.More preferably 11.0～12.0.
Hanging down pH (preferred 6-10) aqueous phase extracted by using with water unmixing or almost immiscible solvent; the free alkali form that separates the enantiomorph of 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives; randomly, it can be converted into its salt through conventional method.
Preferably, this solvent is selected from (C
6-C
8) aromatic hydrocarbon such as toluene or dimethylbenzene; (C
1-C
3) aliphatic chlorides such as methylene dichloride or chloroform, and (C
2-C
8) aliphatic ether such as ether, isopropyl ether or t-butyl methyl ether.
Perhaps, the salt of a kind of purified enantiomorph basically of formula (I) compound can be by handling with the salt of basic metal or alkaline-earth metal and directly obtaining from reaction medium.In preferred embodiments, the salt of basic metal or alkaline-earth metal is the halogenide of basic metal or alkaline-earth metal.In a more preferred embodiment, the halogenide of basic metal or alkaline-earth metal is magnesium chloride.
The invention has the advantages that each of preparation 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives method of purified enantiomorph basically can equally easily provide any enantiomorph.Similarly, the invention provides a kind of simple and efficient way of enantiomorph of preparation 2-(2-pyridylmethyl sulfinyl)-benzimidizole derivatives, gained enantiomorph yield height and optical purity height.In addition, the enantiomorph of opposite absolute configuration can be by racemization, and this makes it possible to by technological process it be reused, and has avoided the loss of raw material.Similarly, resolution reagent can reclaim from organic phase, and can be used in next step production.
In entire description and claims, word " comprises " and the variant of this word is intended to not get rid of other technical characterictic, additive, component or step.The content of the application's summary is incorporated this paper into as a reference.Other target, advantage and the feature of the present invention will become apparent by studying this specification sheets to those skilled in the art, maybe can be understood by implementing the present invention.Following embodiment provides by the mode of explanation, and does not limit the present invention.
Embodiment
Following non-limiting examples has been set forth the configuration of the specific steric isomer of the present invention.When needing other configuration of steric isomer, the present invention can begin from the compound with suitable configuration to carry out with similar methods, and this it will be apparent to those skilled in the art that.
Embodiment 1: preparation S-omeprazole in toluene/heptane and triethylamine
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex
With 10.0g omeprazole (29.0mmol) and 12.4g (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (43.4mmol) is suspended in 96ml toluene, 24ml heptane and the 2ml triethylamine.It is heated 30min in 70 ℃.In 0-5 ℃ of cooling, with the suspended solids filtration and in 40 ℃ of vacuum-dryings.Obtain stoichiometric ratio and be 1: 1 S-omeprazole
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex, yield 94% (proofreading and correct), 97%e.e. (according to HPLC) through HPLC.1H-RMN (400MHz, CDCl
3): δ 11.9 (1H, bandwidth signals), 7.96 (1H, s), 7.86 (2H, d, J=8.9Hz), 7.82 (2H, d, J=8.0Hz), 7.51 (1H, bandwidth signals), 7.32 (4H, m), 7.25 (2H, t, J=8.0Hz), 7.14 (2H, d, J=8.3Hz), 6.89 (1H, d, J=8.5Hz), 6.79 (1H, bandwidth signals), 4.70 (1H, d, J=13.6Hz), 4.63 (1H, d, J=13.6Hz), 3.80 (3H, s), 3.67 (3H, s), 2.17 (6H, s).
Comparative examples 1: preparation S-omeprazole in the benzene/hexane that does not contain amine
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex
For relatively, when not containing triethylamine, prepare the S-omeprazole
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex.With 1.0g omeprazole (2.9mmol) and 1.2g (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (4.3mmol) is suspended in 29ml benzene and the 7ml hexane.It is heated 30min in 90 ℃.In 0/5 ℃ of cooling.With the suspended solids filtration and in 40 ℃ of vacuum-dryings.Obtaining the 1.5g title compound, is 76% through the gauged yield of HPLC, is 61% according to the e.e. of HPLC.
Comparative examples 2: preparation S-omeprazole in the benzene/heptane that does not contain amine
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex
With 20.0g omeprazole (57.9mmol) and 25.0g (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (86.8mmol) is suspended in 600ml toluene and the 150ml heptane.It is heated 30min in 85 ℃.In 0-5 ℃ of cooling, with the suspended solids filtration and in 40 ℃ of vacuum-dryings.Obtain stoichiometric ratio and be 1: 1 S-omeprazole
*(S)-and [1,1 ' dinaphthalene]-2,2 ' diphenol clathrate complex, be 25% through the gauged yield of HPLC, be 94% according to the e.e. of HPLC.
Embodiment 2: preparation S-omeprazole in containing the toluene of triethylamine
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex
With 10.0g omeprazole (29.0mmol) and 12.4g (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (43.4mmol) is suspended in 80ml toluene and the 2ml triethylamine.It is heated 30min in 70 ℃.In 0-5 ℃ of cooling, with the suspended solids filtration and in 40 ℃ of vacuum-dryings.Obtain stoichiometric ratio and be 1: 1 S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-the diphenol clathrate complex, be 89% through the gauged yield of HPLC, be 97% according to the e.e. of HPLC.
1H-RMN (400MHz, CDCl
3): δ 11.9 (1H, bandwidth signals), 7.96 (1H, s), 7.86 (2H, d, J=8.9Hz), 7.82 (2H, d, J=8.0Hz), 7.51 (1H, bandwidth signals), 7.32 (4H, m), 7.25 (2H, t, J=8.0Hz), 7.14 (2H, d, J=8.3Hz), 6.89 (1H, d, J=8.5Hz), 6.79 (1H, bandwidth signals), 4.70 (1H, d, J=13.6Hz), 4.63 (1H, d, J=13.6Hz), 3.80 (3H, s), 3.67 (3H, s), 2.17 (6H, s).
Embodiment 3: recrystallization S-omeprazole in ethanol
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex
With 5.0g S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-diphenol clathrate complex (e.e.95.7%) is suspended in the 95ml ethanol.It is dissolved until product fully in 70 ℃ of heating.Then, in 0 ℃ of cooling.Crystalline solid is filtered, with washing with alcohol and in 40 ℃ of vacuum-dryings.Obtain 3.1g (yield 62%) S-omeprazole
*(S)-[1,1 '-dinaphthalene]-2,2 '-the diphenol clathrate complex, e.e. is 99.7%.
Also carried out crystallization in following solvent, obtained similar result, described solvent is methyl alcohol and Virahol.
Embodiment 4: from the S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole begins to prepare esomeprazole in toluene
By adding NaOH 10%, with 5.0g S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole is dissolved in H
2In the O/ toluene mixture.Adjusting pH is 11.5-12.0, and separates organic phase.Repeat said process until confirm aqueous phase do not have residual (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol.The pH that regulates water is 7.0-7.5, and uses CH
2Cl
2With its extraction.Organic phase is separated, be evaporated to drying, obtain 2.7g esomeprazole (yield 99%).
1H-RMN (400MHz, CDCl
3): δ 12.2 (1H, bandwidth signals), 8.18 (1H, s), 7.3-7.7 (1H, bandwidth signals), 6.7-7.2 (1H, bandwidth signals), 6.92 (1H, dd, J=8.9Hz, J '=2.1Hz), 4.80 (1H, d, J=13.6Hz), 4.74 (1H, d, J=13.6Hz), 3.83 (3H, s), 3.67 (3H, s), 2.23 (3H, s), 2.20 (3H, s).
Embodiment 5: from the S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole begins to prepare esomeprazole in methylene dichloride
By adding NaOH10%, with 1.0g S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole is water-soluble/dichloromethane mixture in.Adjusting pH is 11.5-12.0, and separates organic phase.The pH that regulates water is 7.0-7.5, and uses CH
2Cl
2With its extraction.Organic phase is separated, be evaporated to drying, obtain 0.5g esomeprazole (yield 92%).
Embodiment 6: from the S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole begins to prepare esomeprazole in t-butyl methyl ether
By adding NaOH 10%, with the S-omeprazole of preparation among the 5.0g embodiment 1
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole is water-soluble/the t-butyl methyl ether mixture in.Regulating pH is 11.3, and separates organic phase.The pH that regulates water is 7.3, and with methylene dichloride it is extracted.Organic phase is separated, be evaporated to drying, obtain 2.7g esomeprazole (yield 99%).
Embodiment 7: from the S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole begins preparation esomeprazole magnesium salts in toluene
By adding NaOH 10%, with 10.0g S-omeprazole
*-2,2 (S)-[1,1 '-dinaphthalene] '-preparation of esomeprazole is water-soluble/toluene mixture in.Adjusting pH is 11.5-12.0, and separates organic phase.Repeat said process until confirm aqueous phase do not have residual (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol.Add 70ml H to aqueous phase
2O, adjusting pH is 11.5-12.0.Add 1.6g and be dissolved in 10ml H
2MgCl among the O
26H
2O.Precipitated solid is filtered, use H
2The O washing obtains 4.3g esomeprazole magnesium salts (yield 76%).
Claims (21)
- Each purified basically enantiomorph of a preparation formula (I) racemic compound or its salt, with and the method for solvate,
Wherein, R 1, R 2And R 3Be identical or different group, it is selected from H, C 1-C 3Alkyl, the optional C that is replaced by one or more fluorine atoms 1-C 3Alkoxyl group and C 1-C 3Alkoxy-C 1-C 3Alkoxyl group; And R 4Be to be selected from H and the optional C that is replaced by one or more fluorine atoms 1-C 3The group of alkoxyl group; It is characterized in that described method comprises:A) in the mixture of tertiary amine and suitable solvent, with [1 of replacement, 1 '-dinaphthalene]-2,2 '-one of two kinds of enantiomorphs of diphenol handle formula (I) compound of racemic mixture form, thereby separate by [1 of a kind of enantiomorph of formula (I) compound and replacement, 1 '-dinaphthalene]-2,2 '-clathrate complex that a kind of enantiomorph of diphenol forms;B) be used in the clathrate complex that obtains in the alkali-metal hydroxide treatment abovementioned steps in the mixture of water and organic solvent, thereby free alkali form or its salt form of a kind of enantiomorph of the formula of obtaining (I) compound, wherein said organic solvent and water unmixing or miscible hardly; AndC) if obtained the free alkali form of formula (I) compound enantiomorph, randomly, be translated into its salt form. - 2. method according to claim 1, wherein said solvate are hydrate.
- 3. method according to claim 1, wherein said replacement [1,1 '-dinaphthalene]-2,2 '-the described enantiomorph of diphenol be selected from (S)-(-) of formula (II)-[1,1 '-dinaphthalene]-2,2 '-(R)-(+)-[1 of diphenol and formula (II '), 1 '-dinaphthalene]-2,2 '-diphenol
- 4. according to claim 1-3 any described preparation method, wherein a R 1It is methyl; R 2Be 2,2, the 2-trifluoro ethoxy; And R 3And R 4Be hydrogen.
- 5. according to claim 1-3 any described preparation method, wherein a R 1And R 2It is methoxyl group; R 3Be hydrogen; And R 4It is difluoro-methoxy.
- 6. according to claim 1-3 any described preparation method, wherein a R 1It is methyl; R 2It is 3-methoxyl group-propoxy-; And R 3And R 4Be hydrogen.
- 7. according to claim 1-3 any described preparation method, wherein a R 1And R 3It is methyl; And R 2And R 4It is methoxyl group.
- 8. the preparation method of compound of definition in the claim 7, wherein clathrate complex with (S)-(-) of formula (II)-[1,1 '-dinaphthalene]-2,2 '-diphenol forms.
- 9. according to any described preparation method of claim 1-3, wherein the tertiary amine described in the step a) is triethylamine, Tributylamine or tripropyl amine.
- 10. preparation method according to claim 9, wherein said tertiary amine is a triethylamine.
- 11. according to any described preparation method of claim 1-3, wherein the solvent described in the step (a) is the aromatic hydrocarbon that is selected from toluene and dimethylbenzene; Or aromatic hydrocarbon that is selected from toluene and dimethylbenzene and the C that is selected from hexane, hexanaphthene and heptane 6-C 8The mixture of aliphatic hydrocrbon.
- 12., further comprise described clathrate complex carried out once in The suitable solvent or the several selective crystallization according to any described preparation method of claim 1-3.
- 13. preparation method according to claim 12 wherein carries out clathrate complex once or the used solvent of several selective crystallization is to be selected from C 1-C 4Alcohol; Be selected from the aromatic hydrocarbon of toluene and dimethylbenzene; And the aromatic hydrocarbon and the C that is selected from hexane, hexanaphthene and heptane that are selected from toluene and dimethylbenzene 6-C 8The mixture of aliphatic hydrocrbon.
- 14. according to any described preparation method of claim 1-3, wherein the alkali metal hydroxide described in the step b) is selected from sodium hydroxide and potassium hydroxide.
- 15. preparation method according to claim 14, wherein said alkali metal hydroxide is a sodium hydroxide.
- 16. according to any described preparation method of claim 1-3, wherein the organic solvent described in the step b) is selected from C 6-C 8Aromatic hydrocarbon, C 1-C 3Aliphatic chlorides and C 2-C 8Aliphatic ether.
- 17. according to any described preparation method of claim 1-3, when being included in pH 10.5-12.5, the preparation of the free alkali form of an enantiomorph of wherein said compound (I) separates organic phase, when pH 6-10, use the The suitable solvent aqueous phase extracted, and randomly, the compound that obtains is converted into its salt by ordinary method.
- 18. preparation method according to claim 17, the used solvent of wherein said extraction is selected from C 6-C 8Aromatic hydrocarbon, C 1-C 3Aliphatic chlorides and C 2-C 8Aliphatic ether.
- 19. according to any described preparation method of claim 1-3, one of its Chinese style (I) racemic compound basically the salt of purified enantiomorph directly from reaction medium, obtain by handling with an alkali metal salt or alkaline earth salt.
- 20. preparation method according to claim 19, the salt of wherein said basic metal or alkaline-earth metal is the halogenide of basic metal or alkaline-earth metal.
- 21. preparation method according to claim 20, the halogenide of wherein said basic metal or alkaline-earth metal is magnesium chloride.
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| ES200500546 | 2005-03-03 | ||
| ES200500546A ES2259269B1 (en) | 2005-03-03 | 2005-03-03 | PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 2- (2-PIRIDILMETILSULFINIL) -BENCIMIDAZOL OPTICALLY ACTIVE. |
| PCT/EP2006/060193 WO2006094904A1 (en) | 2005-03-03 | 2006-02-22 | Process for the preparation of optically active derivatives of 2-(2-pyridylmethylsulfinyl)-benzimidazole via inclusion complex with 1,1'-binaphthalene-2, 2'diol |
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| US7507829B2 (en) * | 2002-12-19 | 2009-03-24 | Teva Pharmaceuticals Industries, Ltd | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates |
| KR100641534B1 (en) * | 2005-07-28 | 2006-11-01 | 한미약품 주식회사 | Process of esomeprazole and salts thereof |
| US8404853B2 (en) | 2006-07-05 | 2013-03-26 | Lupin Limited | Process for the preparation of optically pure or optically enriched enantiomers of sulphoxide compounds |
| WO2008149204A1 (en) * | 2007-06-07 | 2008-12-11 | Aurobindo Pharma Limited | An improved process for preparing an optically active proton pump inhibitor |
| NZ585944A (en) * | 2007-12-18 | 2011-11-25 | Watson Pharma Private Ltd | A process for preparation of stable amorphous R-(+)-lansoprazole |
| US8362042B2 (en) | 2008-05-14 | 2013-01-29 | Watson Pharma Private Limited | Stable R(+)-lansoprazole amine salt and a process for preparing the same |
| CN101391993B (en) * | 2008-10-28 | 2012-07-04 | 安徽美诺华药物化学有限公司 | Method for preparing S-omeprazole and salt thereof by forming inclusion complex with (S)-(-)-1,1'-dinaphthalene-2,2'-diol |
| EP2346854A4 (en) | 2008-11-18 | 2012-10-17 | Hetero Research Foundation | Optical purification of esomeprazole |
| EA020429B1 (en) * | 2008-12-24 | 2014-11-28 | Крка, Товарна Здравил, Д.Д., Ново Место | Process for the preparation of esomeprazole |
| WO2011058569A1 (en) | 2009-11-12 | 2011-05-19 | Hetero Research Foundation | Process for the resolution of omeprazole |
| CN102887885B (en) * | 2012-09-26 | 2014-12-10 | 江苏正大丰海制药有限公司 | Preparation method of esomeprazole sodium |
| CN103483407B (en) * | 2013-10-10 | 2015-11-18 | 宁夏启元药业有限公司 | A kind of Matachrom extractive crystallization double solvent and extractive crystallization method |
| EP2980086B1 (en) | 2014-07-29 | 2016-06-15 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Efficient process for the preparation of esomeprazole (S)-binol complex |
| CZ307419B6 (en) * | 2014-10-17 | 2018-08-08 | Vysoká škola chemicko-technologická v Praze | A method of determining the enantiomeric purity of chiral sulfoxides using 1 H-NMR analysis |
| CZ305940B6 (en) * | 2014-10-17 | 2016-05-11 | Vysoká škola chemicko - technologická v Praze | Binaphthalene-based urea for determining enantiomeric purity of chiral sulfoxides using 1H-NMR analysis |
| CN105294544B (en) * | 2015-11-30 | 2017-09-22 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of high purity sodium picosulfate |
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| DE4035455A1 (en) | 1990-11-08 | 1992-05-14 | Byk Gulden Lomberg Chem Fab | ENANTIOMER SEPARATION |
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| SE510650C2 (en) | 1997-05-30 | 1999-06-14 | Astra Ab | New association |
| SE9900274D0 (en) | 1999-01-28 | 1999-01-28 | Astra Ab | New compound |
| TWI289557B (en) | 1999-06-17 | 2007-11-11 | Takeda Chemical Industries Ltd | A crystal of a hydrate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole |
| WO2004002982A2 (en) | 2002-06-27 | 2004-01-08 | Dr. Reddy's Laboratories Limited | A process for preparation of optically pure or optically enriched sulfoxide compounds, including amorphous esomeprazole and salts thereof |
| TW200410955A (en) | 2002-07-29 | 2004-07-01 | Altana Pharma Ag | Novel salt of (S)-PANTOPRAZOLE |
| CN1223262C (en) * | 2003-08-07 | 2005-10-19 | 广水市东晨菌业科技有限公司 | Synchronously cultivating method for rhizoma gastrodiac sexual propagation |
| KR100641534B1 (en) | 2005-07-28 | 2006-11-01 | 한미약품 주식회사 | Process of esomeprazole and salts thereof |
| SI1973896T1 (en) | 2005-12-28 | 2009-08-31 | Union Quimico Farma | A process for the preparation of the (s)-enantiomer of omeprazole |
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- 2006-02-22 WO PCT/EP2006/060193 patent/WO2006094904A1/en active IP Right Grant
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2007
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2008
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1223262A (en) * | 1998-12-28 | 1999-07-21 | 中国科学院成都有机化学研究所 | Inclusion and resolution preparation process of optical purity benzimidazoles medicines resisting peptic ulcer |
| CN1329003A (en) * | 2000-06-19 | 2002-01-02 | 中国科学院成都有机化学研究所 | Preparation method of optical purity lansoprazole |
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Also Published As
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|---|---|
| DK1858881T3 (en) | 2008-12-01 |
| EP1858881A1 (en) | 2007-11-28 |
| WO2006094904A1 (en) | 2006-09-14 |
| NO20074978L (en) | 2007-11-23 |
| HRP20080510T3 (en) | 2008-12-31 |
| ES2259269A1 (en) | 2006-09-16 |
| KR101246479B1 (en) | 2013-03-21 |
| AU2006222032B2 (en) | 2011-03-10 |
| CN101133049A (en) | 2008-02-27 |
| ATE406362T1 (en) | 2008-09-15 |
| PT1858881E (en) | 2008-10-08 |
| CY1108491T1 (en) | 2014-04-09 |
| JP2008531641A (en) | 2008-08-14 |
| MX2007010705A (en) | 2007-11-08 |
| ZA200707335B (en) | 2008-12-31 |
| ES2259269B1 (en) | 2007-11-01 |
| ES2313617T3 (en) | 2009-03-01 |
| DE602006002495D1 (en) | 2008-10-09 |
| US7777044B2 (en) | 2010-08-17 |
| NZ561214A (en) | 2009-09-25 |
| US20080167473A1 (en) | 2008-07-10 |
| KR20070113212A (en) | 2007-11-28 |
| AU2006222032A1 (en) | 2006-09-14 |
| CA2598224C (en) | 2012-08-28 |
| EP1858881B1 (en) | 2008-08-27 |
| CA2598224A1 (en) | 2006-09-14 |
| JP5097559B2 (en) | 2012-12-12 |
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